Inhibition of Intracellular Clusterin Attenuates Cell Death in Nephropathic Cystinosis

Sansanwal, Poonam; Li, Li; Sarwal, Minnie M.

doi:10.1681/asn.2013060577

Cited by 37 publications

(32 citation statements)

References 55 publications

(69 reference statements)

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“…21,22,28 In this context, it is important to note that recent advances in the field of cystinosis have highlighted that aberrant autophagy is an important contributor to the pathogenesis of the disease. 10,29 The discovery of compounds, such as genistein 23 and 2-hydroxypropyl-b-cyclodextrin, 30 able to stimulate endogenous TFEB activity has provided an attractive alternative to gene-transfer therapy in the treatments of diseases that potentially can benefit from TFEB activation. Genistein, a natural isoflavone present in soy, has been proposed as therapeutic agent for the LSD, mucopolysaccharidosis, for its ability to inhibit the synthesis and reduce lysosomal storage of glycosaminoglycans 31 and, recently, for its ability to activate TFEB.…”

Section: Discussionmentioning

confidence: 99%

Activation of the transcription factor EB rescues lysosomal abnormalities in cystinotic kidney cells

Rega

Polishchuk

Montefusco

et al. 2016

Kidney International

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Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disease characterized by accumulation of cystine into lysosomes secondary to mutations in the cystine lysosomal transporter, cystinosin. The defect initially causes proximal tubular dysfunction (Fanconi syndrome) which in time progresses to end-stage renal disease. Cystinotic patients treated with the cystine-depleting agent, cysteamine, have improved life expectancy, delayed progression to chronic renal failure, but persistence of Fanconi syndrome. Here, we have investigated the role of the transcription factor EB (TFEB), a master regulator of the autophagy-lysosomal pathway, in conditionally immortalized proximal tubular epithelial cells derived from the urine of a healthy volunteer or a cystinotic patient. Lack of cystinosin reduced TFEB expression and induced TFEB nuclear translocation. Stimulation of endogenous TFEB activity by genistein, or overexpression of exogenous TFEB lowered cystine levels within 24 hours in cystinotic cells. Overexpression of TFEB also stimulated delayed endocytic cargo processing within 24 hours. Rescue of other abnormalities of the lysosomal compartment was observed but required prolonged expression of TFEB. These abnormalities could not be corrected with cysteamine. Thus, these data show that the consequences of cystinosin deficiency are not restricted to cystine accumulation and support the role of TFEB as a therapeutic target for the treatment of lysosomal storage diseases, in particular of cystinosis.

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Section: Discussionmentioning

confidence: 99%

Activation of the transcription factor EB rescues lysosomal abnormalities in cystinotic kidney cells

Rega

Polishchuk

Montefusco

et al. 2016

Kidney International

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“…This protein was shown to be involved in induction of apoptosis in RPTECs (Sansanwal et al, 2015). Silencing of this gene causes inhibition of apoptosis, indicating that clusterin plays a crucial role in the renal cell injury mechanism (Sansanwal et al, 2015). Among downregulated genes in cells treated with AmB-Cu 2+ complexes were also two genes that were upregulated in cells treated with AmB: STC2 and SOD2.…”

Section: Discussionmentioning

confidence: 99%

Expression profiles of genes related to melatonin and oxidative stress in human renal proximal tubule cells treated with antibiotic amphotericin B and its modified forms

Gola

Skubis²,

Sikora³

et al. 2015

Turk J Biol

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It acts through membrane receptors (MT1 and MT2), nuclear receptors (ROR/RZR -retinoid orphan receptors/ retinoid Z receptors), and nonreceptor-mediated mechanisms (Slominski et al., 2012). Melatonin, through its antioxidant properties, protects against damage of cellular components including DNA, cytosolic proteins, and cell membrane lipids (Yürüker et al., 2015). Studies on the antioxidant properties of melatonin are most commonly associated with agents that induce free radicals in cells (Nazıroğlu et al., 2013). Antibiotics also induce the generation of free radicals. One of them, amphotericin B (AmB), causes lipid peroxidation through generation of reactive oxygen species (ROS). AmB belongs to the group of polyene antibiotics and is an effective antifungal drug commonly used to treat systemic mycoses. It is believed that the fungicidal activity is due to the binding of AmB with the ergosterol present in the cell membrane of fungi, resulting in membrane permeabilization and osmotic imbalance (Brajtburg et al., 1990;Paulo et al., 2013). One of the mechanisms leading to fungal cell death is leakage of potassium ions caused by formation of ion channels in the cell membrane as a consequence of AmB binding with ergosterol (Chudzik et al., 2015). This situation leads to the generation of ROS and lipid peroxidation (Mesa-Arango et al., 2012). Unfortunately, AmB, besides its affinity to ergosterol, also shows an affinity to cholesterol present in human cell membranes, causing nephrotoxic and hepatotoxic side effects (Antonowicz-Juchniewicz et al.

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“…Studies using a cystinotic mouse model have shown decreased expression of the multi-ligand receptors megalin and cubilin in proximal tubules; this was associated with cell dedifferentiation and apoptosis (5,8). Also, enhanced cell death due to activation of proapoptotic signals probably occurs in other tissues (9)(10)(11).…”

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confidence: 99%

Cystinosin-LKG rescues cystine accumulation and decreases apoptosis rate in cystinotic proximal tubular epithelial cells

et al. 2016

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Background: Nephropathic cystinosis is a lysosomal storage disease that is caused by mutations in the CTNS gene encoding a cystine/proton symporter cystinosin and an isoform cystinosin-LKG which is generated by an alternative splicing of exon 12. We have investigated the physiological role of the cystinosin-LKG that is widely expressed in epithelial tissues. Methods: We have analyzed the intracellular localization and the function of the cystinosin-LKG conjugated with DsRed (cystinosin-LKG-RFP) in Madin-Darby canine kidney cells (MDCK II) and in proximal tubular epithelial cells carrying a deletion of the CTNS gene (cystinotic PTEC), respectively. results: Cystinosin-LKG-RFP colocalized with markers of lysosomes, late endosomes and was also expressed on the apical surface of polarized MDCK II cells. Moreover, immuneelectron microscopy images of MDCK II cells overexpressing cystinosin-LKG-RFP showed stacked lamellar membranes inside perinuclear lysosomal structures. To study the role of LKG-isoform, we have investigated cystine accumulation and apoptosis that have been described in cystinotic cells. Cystinosin-LKG decreased cystine levels by approximately 10-fold similarly to cystinosin-RFP. The levels of TNFα-and actinomycin D-inducted apoptosis dropped in cystinotic cells expressing LKG-isoform. This effect was also similar to the main isoform. conclusion: Our results suggest that cystinosin-LKG and cystinosin move similar functional activities in cells.n ephropathic cystinosis (NC) is a rare lysosomal storage disease. It is caused by defective activity of cystinosin, a proton/cystine symporter that is ubiquitously expressed on lysosomal membranes, which leads to cystine accumulation into lysosomes and crystal formations in many tissues (1). One of the first symptoms of NC is renal Fanconi syndrome, secondary to a global dysfunction of proximal tubular cells. During their lifetimes, patients with NC develop several others symptoms in particular, if they are not well treated with cysteamine (2,3).Recent works have demonstrated an involvement of cystinosin in lysosomal kinetics and exocytosis (4), vesicle trafficking (4,5), autophagy, (6) and in sensing cell oxidative state (7). Studies using a cystinotic mouse model have shown decreased expression of the multi-ligand receptors megalin and cubilin in proximal tubules; this was associated with cell dedifferentiation and apoptosis (5,8). Also, enhanced cell death due to activation of proapoptotic signals probably occurs in other tissues (9-11).Cystinosin (accession number: NP_004928) is composed of seven transmembrane domains that bear two lysosomal targeting motifs (GYDQL and YFPQA) and seven N-glycosylation sites in the amino-terminal region (12). The aceview database reports various alternative splicing transcripts for the CTNS gene that encodes the cystinosin (http://www.ncbi.nlm.nih. gov/IEB/Research/Acembly). In 2008, we have identified a 400 amino acid cystinosin isoform that derives from alternative splicing of CTNS gene exon 12 (accession number: NP_001026...

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Inhibition of Intracellular Clusterin Attenuates Cell Death in Nephropathic Cystinosis

Cited by 37 publications

References 55 publications

Activation of the transcription factor EB rescues lysosomal abnormalities in cystinotic kidney cells

Activation of the transcription factor EB rescues lysosomal abnormalities in cystinotic kidney cells

Expression profiles of genes related to melatonin and oxidative stress in human renal proximal tubule cells treated with antibiotic amphotericin B and its modified forms

Cystinosin-LKG rescues cystine accumulation and decreases apoptosis rate in cystinotic proximal tubular epithelial cells

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